Substituted ethylenediamine derivatives



Patented Oct. 6, 1953 rsN'r OFFICE SUBSTITUTED ETHYLENEDIAMINE DERIVATIVES Domenick Papa, Brookl Bronx, and Frank Villa yn, Nathan Sperber, ni, Brooklyn, N. Y., as-

signors to Schering Corporation, Bloomfield,

N. J a corporation of Ne w Jersey No Drawing. Application August 30, 1948, Serial No. 46,924

14 Claims.

The present invention relates to a new group of compounds having useful therapeutic activity. More specifically, the invention relates to amide derivatives of organic carboxylic acids of the following general formula:

2)z l R( o Hip-o ON-YRl wherein R and R1 are selected from aliphatic, cycloaliphatic, aryl and heterocyclic groups, a: is selected from 0, 1 and 2, Y is a saturated aliphatic group containing from 2 to 4 carbon atoms and R2 is a member of the group consisting of dialkylamino, piperidino, morpholino and imidazolinyl groups. The radicals R and R1 in the above general formula may be substituted by lower alkyl groups, lower alkoxy groups, halogen, and basic groups such as amino, dialkylamino, acylamino, and the like.

The compounds of the be prepared by the condensation of a carbocylic acid chloride or a carboxylic acid ester with the appropriately substituted alkylenediamine derivative. The substituted alkylenediamines are readily available by the condensation of an amine with a dialkylaminoalkyl halide. For example, N,Ndimethyl-N'-phenylethylenediamine is obtained by the condensation of aniline and N,N- dimethylaminoethyl chloride in accordance with known methods. Other amines, such as amylamine, benzylamine, 2-aminopyridine, Z-aminothiazcle, and the like can be used in a similar reaction to obtain the desired substituted alkylenediamine. In place of the c-N,N-dimethylaminoethyl chloride, other appropriately substituted amines, such as ,c-N,N-diethylaminopropyl chloride, fi-N-piperidinoethyl chloride, fl-N-morpholinoethyl chloride and fi-N-imidazolinylethyl chloride can be used.

The compounds of the present invention may be used in the form of tablets into which are incorporated either the free base or its salt. Typical salts which may 'be used are the hydrochloride, the phosphate, the succinate, the maleate, and the tartrate.

The following examples will illustrate the methods and compounds of the present invention and are not intended to restrict the scope of the invention:

EXAMPLE I N ,N -dz'methyl-N pz'colz'noyl N phenylethylenediamzne Method I.Thirty-five cc. of thionyl chloride are added slowly with stirring and cooling to present invention may f 12.8 g. picolinic acid. After hour on the steam bath, the excess thionyl chloride is removed in vacuo. To the resulting picolinoyl chloride hydrochloride, 30 g. triethylamine in 150 cc. dry benzene is added slowly with efficient cooling and stirring then 16.5 g. N,l\T-dimethyl-N-phenylethylenediamine in cc. dry benzene is added. The mixture is refluxed for 8-12 hours on the steam bath with stirring. After cooling, the reaction product is poured on ice water, made alkaline with sodium hydroxide and extracted with ether. The ether extracts are extracted with dilute (10%) hydrochloric acid. The acid extracts are made strongly alkaline and the resulting oil extracted with ether. The ether extracts are dried over anhydrous sodium sulfate and the solvent then removed. The residue is distilled and a light yellow viscous oil boiling at 175-180 C. at 2 mm. is obtained.

The picolinamide of this example may also be obtained by method II: A mixture of 15.1 g. ethyl picolinate and 32.8 g. N,N-dimethyl-N' phenylethylenediamine is heated with stirring at 170-190 C. for 40-60 hours. The resulting mixture is distilled under reduced pressure to yield the amide of this example.

EXAMPLE 1::

g. nicotinic acid and ml. thionyl chloride is refluxed on the steam bath for two hours. The excess thionyl chloride is removed in vacuo and to the crystalline residue of nicotinoyl chloride hydrochloride, 200 cc. dry pyridine is added slowly With cooling. Then 64 g. of N,Ndimethyl-N-phenyl ethylene diamine is added and the mixture refluxed with stirring for 8-12 hours. The excess pyridine is removed in Vacuo and the viscous residue is poured on ice and water. The aqueous mixture is made alkaline with sodium hydroxide, extracted with ether and the amide purified as described under method I of Example I. The nicotinoyl amide is obtained as a yellow oil boiling at 174-177 C./0.5 mm.

A mixture of 44.3

EXAMPLE III N,N-dicthyZ-N-nicotinoyl N phenylethylenediamine A mixture of 36 g. nicotinoyl chloride (J. Org. Chem. 10, 27 (1945)) and 48 g. of N,N-diethyl- N-phenylethy1enediamine in 200 cc. anhydrous benzene is refluxed with stirring for 18 hours. The mixture is poured on ice water andv the amide is isolated by method I of Example I. This amide is also a light yellow viscous oil boiling at l85-190 C./ 0.5 mm.

This compound may also be made in high yield by the method of Example II.

EXAMPLE IV N ,N dimethyl-N nicotinoyl N (p-methylph enyl) ethylenediamine This compound is prepared by? the methodof Example II using N,N-dimethyl-N-(p-methyh.

phenyl) ethylenediamine and nicotinoyl chloride 4. l

hydrochloride. C./0.5 mm. after distillation and melts. at '7373.5 C.

EXAMPLE V N ,N -dimethyZ-N '-nicotinoyl-N (m-chlo r'oqw phenyl) ethylenediamine This amide is prepared by the method 'of Example II using N,N-dimethyl-N-(In-chlorophenyl) ethylenediamine; It boils at 176-185" C./0.5,mm. and melts, after recrystallization from lig roin, at 74-745 C.

EXAMPLE VI N ,N -'dimethyZ-N '-nicotinoyZ-N (p-chlor'ophenyl) ethylene diamine By the method of ExampleII, this amide. is obtained 4 from N,N-dimethyl-N (p-chlorophenyl) ethylenediamine as a light yellow, .viscous oil Inplace of the'dimethyl'compound'of the pre-* vious example; N,N -diethyl-N' -benzylethylenediamine-is used to obtain the amide of thisex'- ample; It is: a yellow, viscous liquid distilling at 185-l90 -C;/l mm.

EXAMPLE X N ,N -d i'meihyZ -N -nz'cotinoyZ-N' (p-chlorobenzyll ethylenedz'amine The condensation of N,N-dimethyl-N-(pchlorobenzyl) ethylenediamine and nicotinoylchloride. hydrochloride gives at 190195 C./1-2Vmm..

EXAMPLE XI V N ,N -dimethg Z-N -nicotinoyl-N' (p-methylbenzyl) ethylenedz'amine By the'condensation of the appropriatelysubstituted 7 benzylethylenediamine and nicotinoyl chloride hydrochloridepthe amide of this example is obtained as a yellow; viscous at '188-190C./0.5 mm.

this amide boiling Oil boilin The amide JbOiIS- at 180-189 A "3 EXAMPLE XII N ,N -dimethyZ-N -nicotz'n0yl-N (p-methozcybenzyl) ethylenediamine :The -N;N .dimethyl-N"p methoxyhenzyl) ethylene'diam-ine condensed with nicotinoyl chloride hydrochloride as described in Example II gives this amide boiling at l-194 C./1 mm.

EXAMPLE XIII I N ,N -dimethyZ-N -pzcolinoyZ-N (ya-methylphenyl) 'ethylenediamine By condensing N,N-dimethyl-N (p-methylphenyl)Hethylenediamine with picolinoyl chloride hyhrochloride by method I of Example I, there is obtained the amide of this example which disti-llsa't -189 C./1 mm.

EXAlVIPLE XIV N ,N -dimethyZ-N -picoZinoa Z-N "(777rChZOTO1 phenyl); ethylenediamine This amideris prepared \from ILN-dimethyla: (m-chlorophenyl). ethylenediamine in accord ance with method I of Example' I. The amide" is a yellow, viscous, liquid distilling at 182- l86 C./l2 mm.

EXAMPLE XV N,N-dimethyZ-=N. -picoZi1royZ-N"- (p-chZomphenyZ-y:

ethylenediotmi-ne By substituting the p-chlorocompound for the meta compound of the previous example; this amide is obtained as a viscous liquid which'dis-' tills at 1'85-l90C./12'mm.

EXAMPLE XVI N,N dimcthyZ-'N"-picoZinogZ-N' ('o-methoxyphenyl) ethylenediamine By using the 0-.methoxyphenylsub'stitutedethylenediamine in accordance withvmethod 0f- Example I, the amide of this example-is obtained boiling ,at. ISO-194 .C./1-2 mm..-

EXAMPLE XVII BIN-dimethyZ-N' picolinoyl-N' -benzyZethyZene- 1 diamine.

By using the benzyl: substituted ethylenediamine in accordance with methodl'of Example I; there is obtained the amideof this "example boiling at'180-186-C./1 mmx EXAMPLE XVIII By using the p-chlorobenzyl substituted ethyl..- enediamine in accordance with method I of Example I, there is obtained the amide of this example which boils at l90-192 C./ 1-2 mm.

EXAMPLE XIX N ,N -dimethyZ-N -picoZinoyZ-N (xi-methylbemzyl) ethylenediamme By using the p-methylbenzyl substituted: ethylenediamine in accordance with'method'l'of Example-L-there is-pbtained the amide of this example which boils at 188-192" C./1 mm.

EXAMPLE XX N ,N -=dimethyZ-N "-picoZino'Jl-N (p-methoxybenzyl) ethyZe-nediwmine Byu's-i-ng the p-methoxybenzyl substituted ethylenediam ine in accordance with method I of Example I, there is obtained the amide of this example boiling at 190-19 1 C./0.5 mm.

The following further compounds are representative of those within the scope of the present invention. The methods described above can be used in the preparation of these compounds. The intermediate products, namely, the acid chlorides and the unsubstituted amines, are readily available by well-known methods described in the chemical literature.

1. N,N-dimethyl N (2 methylthienyl) -N- (fi-chloronicotinoyl) -l,2-diaminopropane.

2. N ,N -dimethy1-N -benzyl-N' -2-thenoylethylenediamine.

3. N,N-dimethyl N benzyl-N'-1-naphthoylethylenediamine.

4. N,N-dimethyl-N-benzyl-N-(p chlorobenzoyl) ethylenediamine.

5. N,N-diethyl N benzyl N thenoyl) ethylenediamine.

6. N,N-dimethyl-N-(p dimethylaminophenyl) -N-picolinoylethylenediamine.

7. N,N climethyl-N-benzyl-N'-(tributylacetyl) ethylenediamine.

8. N,N-dimethyl-N-benzyl N benzoyl) ethylenediamine.

9. N -benzyl-N- fi-l-piperidinoethyl) coumarilamide.

l0. N,N dimethyl-N'-phenyl-N-(a-ar-tetrahydronaphthaleneacetyl) ethylenediamine.

l1. N,N-dimethyl-N-(p methoxyphenyl) -N- (a-ac-tetrahydronaphthaleneacetyl) ethylenediamine.

12. N-(s-dimethylaminoethyl) thiazylcarboxamide.

13. N,N-dimethyl-N -benzyl-N-furoyl-l,3-diaminopropane.

14. N,N-dimethyl-N-(2-thiazyl) -N-nicotinoylethylenediamine.

15. N-(s-dimethylaminoethyl) methyl-2-pyrazinecarboxamide.

16. N,N dimethyl-N-2-pyridyl-N-nicotinoylethylenediamine.

We claim:

1. Compounds of bases of the formula Py-C OI T(CH2)2N-(R2)2 wherein Py is a pyridine ring, R1 is selected from the group consisting of phenyl, benzyl and the monolower alkyl, mono-chloro and monolower alkoxy ring substitution products and R2 is a lower alkyl group, and the non-toxic salts thereof.

- (4 methyl- (hexahydro- N benzyl-z- N phenyl-6- the group consisting of 2. Compounds of the general formula Ulla- 1 Py-CON-(CHM-N-(Rz): wherein Py is a pyridine ring, R1 is a phenyl nucleus, and R2 is a lower alkyl group.

3. Compounds as defined in claim 2 wherein the phenyl nucleus contains one chlorine.

4. Compounds as defined in claim 2 wherein the phenyl nucleus contains one lower alkyl group.

5. Compounds as defined in claim 2 wherein the phenyl nucleus contains one lower alkoxy group.

6. Compounds of the general formula R1 Py-C 01 I( CH2)2-N-(Rz)z wherein Py is a pyridine ring, R1 is a phenyl nucleus, and R2 is a lower alkyl group.

7. Compounds as defined in claim 6 wherein the phenyl nucleus contains one chlorine.

8. Compounds as defined in claim 6 wherein the phenyl nucleus contains one lower alkyl group.

9. Compounds as defined in claim 6 wherein the phenyl nucleus contains one lower alkoxy group.

10. N,N dimethyl N phenylethylenediamine.

- picolinoyl N 11. N,N dimethyl N nicotinoyl N (p chlorophenyl) ethylenediamine.

12. N,N dimethyl N picolinoyl N (p chlorophenyl) ethylenediamine.

l3. N,N dimethyl N nicotinoyl N (p methylphenyl) -ethylenediamine.

14. N,N dimethyl N picolinoyl N (p methylbenzyl) -ethylenediamine.

DOMENICK PAPA. NATHAN SPERBER. FRANK VILLANI.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 1,737,458 Hartman Nov. 28, 1929 1,886,481 Hartman Nov. 8, 1932 OTHER REFERENCES Gryszkiewicz, Chemical Abstracts, Vol. 32, p. 4604.

Wiselogle, Survey of Antimalarial, p. 497, SN 10950, 1946, vol. II, part 1. 

1. COMPOUNDS OF THE GROUP CONSISTING OF BASES OF THE FORMULA 